Bone metabolism - an underappreciated player

Abstract

Bone is constantly being remodeled, and this process is orchestrated by a dynamic crosstalk of bone cells, including osteoclasts, osteoblasts, and osteocytes. Recent evidence suggests that cellular metabolism plays a crucial role in the differentiation and function of bone cells and facilitates the adaptation of bone cells to changes in the bone microenvironment. Moreover, bone affects whole-body energy metabolism. However, it is not yet completely understood how different cells in bone coordinate metabolic processes under physiological conditions, and how altered metabolic processes in bone cells contribute to pathological conditions where the balance among bone cells is disrupted. Therefore, gaining a better understanding of the distinct metabolic requirements of bone cells can provide crucial insights into the dysfunction of bone cells in pathological conditions and can be used to identify new therapeutic approaches to treat bone diseases. Here, we discuss recent advances in understanding metabolic reprogramming in bone cells.

Fig. 1. Bone remodeling.

Bone remodeling is a fundamental process to maintain bone throughout life. It involves the removal of old bone tissue by osteoclasts and subsequent formation of new bone formation by osteoblasts. Maintaining a balance between these two types of cells is tightly regulated and essential for healthy bone homeostasis. Osteoclasts are multinucleated cells that originate from myeloid lineage cells. Osteoclasts are multinucleated cells that originate from hematopoietic stem cells. Osteoclast precursor cells fuse with each other to form these multinucleated cells. The formation of osteoclasts is activated by RANKL. On the other hand, mesenchymal stem cells differentiate into osteochodroprogenitors. Osteochondroprogenitor cells further differentiate into preosteoblasts that eventually mature into osteoblasts. A subpopulation of osteoblasts undergoes terminal differentiation to osteocytes which are embedded within the bone tissue. Osteocytes play a crucial role in controlling both osteoblasts and osteoclasts.

Fig. 2. Energy metabolism.

In bone cells, energy is generated by interconnected metabolic pathways, including glycolysis, the tricarboxylic acid cycle (TCA cycle), glutaminolysis, and oxidative phosphorylation (OXPHOS). Glucose is the primary energy and carbon source for bone growth and development. The transportation of glucose by glucose transporter (GLUT) proteins occurs spontaneously along a concentration gradient, without the need for energy. Once inside the cell, glucose is converted to glucose-6-phosphate (G6P) by hexokinase, which can then be used to generate glycogen or enter the glycolytic pathway to generate pyruvate. Glycolysis coupled with lactic acid fermentation and oxidative phosphorylation in the mitochondria produces adenosine triphosphate (ATP), the most important high-energy chemical in the body. Lactate dehydrogenase (LDH) can also convert glucose to lactate independently of oxygen through aerobic glycolysis. The glucose 6-phosphate, produced early in glycolysis, can be directed towards the pentose phosphate pathway, leading to nucleotide synthesis, or it can contribute to the serine synthesis pathway, which is important for amino acid production. The serine biosynthetic pathway, which generates methyl groups for DNA and histone methylation, is also vital for one-carbon metabolism. OXPHOS occurs in the mitochondria and is the final metabolic pathway for all oxidative steps in carbohydrates, amino acids, and fatty acid catabolism. The electron carriers NAD+ and NADP+ drive the ETC for oxidative phosphorylation, resulting in the production of ATP. The Krebs cycle, also known as the tricarboxylic acid cycle (TCA), is the primary metabolic pathway that produces energy in cells and provides reduced co-factors and metabolic intermediates. Acetyl CoA, derived from pyruvate, is also supplied by the TCA cycle and acts as a central hub to promote intracellular lipid synthesis. Parallel to these processes, glutamine is metabolized through glutaminolysis, contributing to the pool of substrates necessary for energy production and biosynthesis in bone cells. TCA cycle tricarboxylic acid cycle, Acetyl CoA acetyl coenzyme A, NAD+ nicotinamide adenine dinucleotide, NADP+ nicotinamide adenine dinucleotide phosphate, ETC electron transport chain, ATP adenosine triphosphate.

Fig. 3. Fatty Acids regulate bone cells.

Fatty acids are classified according to the presence and number of double bonds in their carbon chain: saturated fatty acids (SFA) contain no double bonds, monounsaturated fatty acids (MUFA) contain one, and polyunsaturated fatty acids (PUFA) contain more than one double bond. There are numerous types of SFA according to the length of their chain (containing 4–16 carbon atoms). PUFAs, such as alpha-linolenic acid (an omega-3 fatty acid) and linoleic acid (an omega-6 fatty acid), are called essential fatty acids because they are precursors to vitamins, cofactors, and derivatives, but our body cannot synthesize them. Fatty acids have both positive and negative effects on the regulation of osteoclasts (green cells and lines) and osteoblasts (orange cells and lines).